There are nearly 24 million people in the U.S. who suffer from diabetes and all are at risk for developing diabetic macular edema (DME), a vision-threatening retinal complication of diabetes that is the leading cause of blindness in working age adults. Current prevalence of DME in the U.S. is estimated to be between 1.2 - 2.1 million. Increased retinal vascular permeability (RVP) to plasma proteins and fluid, resulting from breakdown of the blood-retinal barrier, leads to a build-up of fluid in the central portion of the retina - the macula - and the development of DME. The serine protease plasma kallikrein (PK) has been recently implicated as a pathological mediator of increased RVP in diabetes. In work carried out in phase I and phase II, ActiveSite has developed novel potent and selective PK inhibitors that reduce pathological RVP induced in clinically relevant rodent models of hypertension and diabetes following systemic, non-ocular administration. Based on efficacy and safety studies carried out in phase II, a lead PK inhibitor has been identified that has been shown to be effective in lowering pathological RVP following daily oral dosing at a moderate daily dose level. Repeat-dose range-finding toxicology studies in rats with the lead compound resulted in dose- proportional drug exposure, and, importantly, did not result in detectable adverse effects on any parameter at the highest dose tested, a dose that resulted in daily exposure to the active compound >40-fold higher than that seen at the efficacious dose, predictive of a high therapeutic index in the clinic. Based on the efficacy and preliminary safety assessments, the specific aims of this competitive phase II renewal application are to carry out FDA-required safety and toxicology studies with the lead PK inhibitor, studies that once completed successfully, would allow for the compilation and filing of an IND application with the FDA for initiating first-in-human Phase I clinical trials for oral treatment for DME. PUBLIC HEALTH RELEVANCE: This phase II project proposes that inhibition of the serine protease plasma kallikrein (PK), would have significant therapeutic impact in reducing diabetic macular edema (DME), the major vision-threatening complication of diabetes. It seeks to carry out FDA-required safety and toxicology studies with an orally active lead PK inhibitor, studies that once completed successfully, would allow for the compilation and filing of an IND application with the FDA for initiating first-in-human Phase I clinical trials for oral treatment for DME.